The long-term goals of this project are to define the molecular, cellular and genetic mechanisms that regulate the development of asthma and allergic diseases. During the previous application period we studied processes that promote and intensify Th2 biased immune responses. We now propose to examine immune mechanisms that prevent the development of Th2 responses, and that reverse established Th2-biased responses in asthma and allergic diseases. Specifically, we will examine the protective effects against allergic disease and asthma afforded by antigen-specific T-cell tolerance induced following respiratory exposure to antigen, and protection induced by immunization with the adjuvant heat killed Listeria monocytogenes (HKL) a potent stimulator of the innate immune system. We have exciting preliminary data demonstrating that respiratory exposure to allergen induces T-cell tolerance, which prevents the development of Th2 responses and airway hyperreactivity, and which is actively mediated by pulmonary dendritic cells that transiently produce IL-10. We will study the role of pulmonary dendritic cells and define the cellular and molecular events by which respiratory antigen induces T-cell tolerance. In addition, we will examine the relationship of T-cell tolerance to immune modulation induced by HKL as adjuvant, and investigate the role of TGF-beta, IL-10, CD8 cells, and Toll-like receptor signaling during the down-regulation of established Th2 biased responses by HKL Finally, using a unique congenic BALB/c mouse strain that resists the development of airway hyperreactivity and produces low levels of IL-4, we will characterize a specific genetic element, Tapr, that we have identified on chromosome 11 and which down-modulates the development of airway hyperreactivity and IL-4 production in CD4+ T-cells. These studies will delineate the cellular and molecular basis for immunoregulation of Th2 responses in asthma and allergy, and should lead to novel therapeutic approaches for asthma and allergic disease. Such therapies will not only eliminate Th2 inflammation, but also replace allergic inflammation with "protective" immunity that potentially will provide long-term cure for asthma and allergic diseases.